The objectives of this project are to identify and characterize the mechanisms by which autosomal dominant, histocompatibility-linked immune response (Ir) genes regulate humoral and cell-mediated responses to T cell-dependent antigens. The immune responses by inbred strains of mice to the synthetic terpolymer L-glutamic acid-L-alanine-L-tyrosine (GAT) and to heterologous insulins are two model systems currently under investigation. The immune response to both of these antigens is all-or-none, that is some strains of mice respond whereas other do not. Continuing studies on the more well-characterized GAT system will focus on functional, serological and immunochemical differences between T cells and B cells from responder and nonresponder mice. During the past two years, assays have been developed for the measurement and characterization of insulin-specific antibodies in serum and produced by single cells. We are currently determining the optimal conditions for development of immune responses to insulin in vitro. Once this techlnology is established, the expression of insulin-specific Ir genes in T cells, B cells and macrophages will be determined. The identification of defects in genetic nonresponder mice should provide valuable insight into regulatory pathways that control the immunological network. In addition, insulin is a biologically active molecule of clinical relevance. It is well-established that insulin replacement therapy frequently results in complications of immune responses to insulin may contribute to the development of rational approaches for manipulation of the immune system to prevent specific antibody responses in insulin-dependent diabetic patients.